3,6-Dioxa-1,8-octandiamido bis (pyridinium) compounds

ABSTRACT

A pyridine derivative of the formula:   wherein R1 and R2 which may be the same or different are each alkyl having 8 to 14 carbon atoms, n-undec-10-yl, 2-nhexyloxyethyl, 2-(2-butoxyethoxy)-ethyl,3,4-dichlorophenyl, 4chlorobenzyl, 2,4-dichlorobenzyl or 2-naphthylmethyl; A1 and A2 are each a direct linkage or a linking group of the formula CH2CO.NH-wherein the methylene is joined to the pyridine nitrogen; (X1.X2)2 represents two monoanions or a dianion selected from the group consisting of two halide, methanesulphonate, toluene-p-sulphonate or acetate ions or the sulphate dianion; and A3 is a linking group of the formula: NH.CO(CH2OCH2)2 CO.NH- . A process for making these salts, compositions containing them and methods of precenting the growth of, or killing, bacteria by applying one of these salts to a bacterially infected environment are also disclosed.

United States Patent Edwards Nov. 4, 1975 1 3,6-DIOXA-l,8-OCTANDIAMIDOBIS (PYRIDINIUM) COMPOUNDS [75] Inventor: Philip Neil Edwards,Macclesfield,

England [73] Assignee: Imperial Chemical Industries Limited, London,England 22 Filed: Dec. 27, 1973 [21] Appl. 190.; 428,694

Related US. Application Data [62] Division of Ser. No. 234,648, March14, 1972, Pat.

[30] Foreign Application Priority Data Mar. 29, 1971 United Kingdom8071/71 [52] US. Cl. 260/2955 A; 260/295 PA; 260/294.8 R

[51] Int. Cl. C07D 31/28 [58] Field of Search 260/295 PA, 295.5 A,

260/294.8 R, 295 E, 295 AM-295 Q, 260/2955 D, 296 D [56] ReferencesCited UNITED STATES PATENTS 2,520,902 9/1950 Bersworth 260/295 R3,786,058 i/1974 Edwards 260/294.8 R

Primary Examiner-Henry R. Jiles Assistant Examiner-Robert W. RamsuerAttorney, Agent, or Firm-Cushman, Darby & Cushman [57] ABSTRACT Apyridine derivative of the formula:

linking group of the formula:

NH.CO(CH2OCHZ)2 CO,NH-

A process for making these salts, compositions containing them andmethods of precenting the growth of, or killing, bacteria by applyingone of these salts to a bacterially infected environment are alsodisclosed.

4 Claims, No Drawings 3-,6-DIOXA-1,8-OCTANDIAMIDO BIS (PYRIDINIUM)COMPOUNDS 5 'This is a division of application- Ser.;-"No;,23 l,648,

filed Mar: l4, 1972-, and-now US. Pat. No. 3,786,058; This inventionrelates to novel' pyridine derivatives which possess valuableantibacterial properties and some of which are useful .indental hygiene"for inhibiting the formation of-dental plaque. Y X 10 According to theinvention there is p'rovideda pyridine derivative of the formula'i tcals of l to 6 carbonatoms; A. and. A which may be the same or differentare each a direct linkage or a linking group of theformula -CH CO-NH.'wherein the methylene radical is joined to the pyridine nitrogen atom;(X! X represents two monoanions or a dianion; and is a,linking groupselected from I i 2...CH:CH I q 3. -(CH ),,O(CH provided that both nsare n -H t 4. (CH ),,'N(COR )(CH wherein R an alkyl or aryl radical ofup to 10 carbon atoms, and provided that both ns are not 0,

koxyalkoxyalkyl, alkanoyloxyalkyl oraryloxyalkyl radicals, they arepreferably straight-chain such radicals, for example n-octyl, n-nonyl,n-decyl, n-undecyl, n--

dodecyl, n-tetradecyl, n-undec-lO-enyl, Z-n-hexyloxyethyl or2-(2-butoxyethoxy)ethyl radicals. When R and R are phenyl or naphthylradicals" containing 0 to 3 halogenatoms, or are alkyl radicals of 1 to3 carbon atoms substituted by a phenyl or naphthyl radical which isitself substituted by O to 3' halogen atoms or alkyl or alkoxy radicalsof l to 6 carbon atoms, such halogenj atoms may be, for example,chlorineor bromine atoms, and the alkyl radical. of l.to 3 carbon atomsmay be, for example, the methyl radical, so that R andR- may be, forexample, 3,4-dichlorophenyl, 4- chlorobenzyl, 2,4-dichlorobe'nzyl or2-naphthylmethyl radicals.

When (X X represents two monoanions, suitable anions are, for example,halide anions, for example chloride orv bromide anions, anions derivedfrom a carboxylic acid, for. example the acetate anion, or

1 anoins derived from asulphonic acid, for' example themethanesulphonate or toluene-p sulphonate anions; and'when (X. Xrepresentsa-dianion, a suitable anion is, forexarnple, .the sulphate orphosphate anion.

It is to be understood that although (X "X represents two monoanions oradianion, the corresponding monovalent radicals or atoms are X and X andthe corresponding divalent radical is (X X ,Thus, for example, X and Xmay each be chlorineor bromine atoms, or methanesulphonyl,toluenesulphonyl or acetoxy radicals, and X .X niay be, f or example,the sulphate divalent-radical. i y I A suitable phenylene orriaphthyle'ne radical is, for example, the o-phenylene, m-phenylene,p-phenylene, 1,4-naphthylene, 1,5-naphthylene, 4-methyl-l,2-phenylene,2,5-dimethyl-1,4:phenylene,. 2,5 -dir'nethoxy- 1,4-phenylene or 2,4,5,6-tetrachlor o-l,3-phenylene radical. l

A suitable value for Z is, for exa'mple, the ethylene, trimethylene,hexamethylene or. 2,2-diethyltrjimethylene radical. 1 i i Preferredlinking groups are those numbered 1, 2, 6, 8, 9,11,12,14, 15,17,18, 23,24, 2 5, 26, 27, 28 and 29 in the list above, and of these, particularlinking Niico- Preferred compounds of the invention are those whereinthe radicals AR and A"R are the same, and a preferred group of pyridinederivatives of the invention comprises those compounds of the formula IA particularly preferred sub-group within the above group comprisesthose compounds wherein A and A are each a direct linkage, R and R areeach an unbranched alkyl radical of 8 to l 1 carbon atoms, option-- allycontaining a terminal double bond, (X X represents two bromide,chloride, methanesulphonate, toluene-p-sulphonate or acetate anions, orthe sulphate dianion, and A is the trimethylene or ureylene radical or aradical of the formula NH-CO(Cl-l CO-Nl-l, and especially thosecompounds wherein A is linked to the same numbered carbon atom of eachpyridine ring.

Particular new pyridine derivatives of the invention are described inExamples 1 to 4, and of these, individ- 4. ml, specially preferredderivatives are 4,4-trimethylenebis( l-n-decylpyridiniummethanesulphonate), (compound 5); 3,3 -ureylene-bis( l-n-decylpyridiniummethanesulphonate (compound 25); 3 ,3 ureylenebis( l-n-decylpyridiniumchloride), (compound 26); 3,3'-glutaramidobis( l-n-decylpyridiniumchloride), (compound 78); 3,3'-glutaramidobis( l-ndecylpyridiniummethanesulphonate), (compound 79); 3 ,3 '-adipamidobis(1-n-decylpyridinium methanesulphonate), (compound 30); 4,4-adipamidobis(l-ndecylpyridinium methan esulphonate), (compound 82); 3 ,3-pimelamidobis-( l-n-decylpyridinium chloride), (compound 86); 3,3-suberamidobis( l-n-decylpyridinium chloride), (compound 87); 3,3-suberamidobis( l-n-decylpyridinium methanesulphonate), (compound 88);3,3-azelamidobis( l-n-decylpyridinium methanesulphonate), (compound 90);3,3- sebacamidobis( l-n-octylpyridinium methanesulphonate), (compound31); and 3,3-sebacamidobis(l-ndecylpyridinium methanesulphonate),(compound 32).

According to a further feature of the invention there is provided aprocess for the manufacture of the novel pyridine derivatives of theinvention which comprises:

a. the quatemisation of a pyridine derivative of the formula:

with a quatemising agent (RA) X, wherein A, A A, R, R X and X have themeanings stated above;

c. for those compounds wherein the linking group A contains one or twoamide linkages, the reaction of a mono-carboxylic acid of the formula:

COOH. (x') 1 ".5 or a reactive derivative thereof, with a suitablemonobasic or dibasic compound, or the reaction of an amine of theformula: 8n

wherein A, R, X and n have the meanings stated above, with a suitablemonobasic or dibasic compound;

e. for those compounds wherein the linking group A contains one urealinkage and which are symmetrical,

the reaction of an amino compound of the formula V wherein A, R, X and nhave the meanings stated above, with a carbonyl compound of the formula(R -CO, wherein R is a chlorine atom, a lower alkox radical or a phenoxyradical; or

with a suitable di-isocyanate, or the reaction of an isof. forthose-compounds wherein the linking group A? contains two urethanelinkages, the reaction of an amino compound of the formula V with asuitable bischloroformate ester, or the reaction of a chloroformateester of the formula:

cu imococi. (X) vn 65 hard water, or.hav1ng more :surface activity.Further,

cyanate-of the formula:

with a suitable dihydroxy compound wherein A, R, X and n have themeanings stated above; or

h. for those compounds wherein the linking group A contains one or twoolefinic linkages, the reaction of an activated methylpyridinium salt ofthe formula:

wherein A, R and X have the meanings stated above, with asuitable monoordi-aldehyde; whereafter if desired a product thus obtained'containing ananion (X (X) or (X X) is converted to a corresponding compoundcontaining a different anion (X) (X or (X X5 by basification thereoffollowed by reaction of the basified product with an acid l-lX, l'lX orH (X X wherein X, X X and X have the meanings stated above, or by anion-exchange resin.

The quatemisation process is preferably carried out by heating togetherthe pyridine derivative and quaternising agent, and the inclusion of asolvent, for example nitrobenzene, sulpholane or toluene, is oftenadvantageous in improving the mutual solubilities of the reactants, orto moderate the reaction. The addition of a tertiary amine, for examplea hindered tertiary amine such as di-isopropylethylamine is also useful,for removing any acid generated duringthe reaction.

The processes"(c) to (h) for the formation of amide, urea, urethane orolefin linkages may be carried out in generally known manner describedin the literature for analogous compounds.

A suitable strong acid HX HX or l-l (X X) has a pK, value of less than2, and is, for example, hydrochloric, hydrobromic, methanesulphonic,toluene-p-sulphonic or sulphuric acid.

As stated above, the new compounds of the invention possess valuableantibacterial properties, in that they are effective against a widerange of both Gram-positive and Gram-negative organisms, includingstrains of, for example, Pseudomonads which are resistant to otherwidely-used antibacterial agents; Further advantages of the preferredcompounds of the invention may include, for example, rapid speed ofkill, being bactericidal rather than bacteristatic, not beingdeactivated by textile materials which have been in contact with thecompounds of the invention are not stained by treatment withhypochlorite bleach.

Thus, according to a further feature of the invention, there is provideda composition comprising at least one pyridine derivative of theinvention together with an inert diluent or carrier.

The composition of the invention may be a pharmaceutical composition,for example in the form of a 102- enge suitable for oral administration,or an ointment, cream, or sterile aqueous or oily solution or suspensionfor topical use; or it may be a non-pharmaceutical composition, in theform of, for example, a non-sterilised aqueous or oily solution orsuspension, or an aerosol, for use as a general, enviromental antisepticor disinfectant, or a mouthwash, paste, gel or fluid suspension suitablefor use in dental hygiene for the inhibition of dental plaque formation.

The composition may contain conventional excipients and carriers, andmay be manufactured by the application of conventional techniques.

Preferred pharmaceutical compositions of the invention are lozenges,each containing from 0.1 to 1.0% w/w of a new compound of the invention,and preferred non-pharmacutical compositions are an aqueous solutionsuitable for use as an antiseptic and containing from 0.02 to 1.0% w/vof a compound of the invention,

(at user dilution) of a compound of the invention; and toothpastes anddental gels containing between 0.05% and 1.0% w/w, preferably between0.1% and 0.5% w/w, of a compound of the invention.

The invention is illustrated but not limited by the following Examples:

EXAMPLE 1 General procedure for quaternisation The pyridine derivative(0.01 mole) and the alkylating agent (0.02-0.1 mole) are heatedtogether, optionally with inclusion of a solvent, e.g. nitrobenzene toimprove the mutual solubilities, or to moderate the reaction, and/or ahindered amine, for example di-isopropylethylamine to remove any acidgenerated during the reaction. The temperature and time of heating areshown for each compound in the Tables, but these are not necessarilyoptimal conditions and they can usually be varied over wide ranges.Theproduct is crystallised from a suitable solvent and, if required, theanion can be changed by conventional procedures, for example by the useof ion-exchange resins.

an aqueous solution in the form of a concentrate con- 25 taining from 1%w/w to that percentage WlllCh gives a saturated solution of a compoundof the invention, or i powder or tablets for dissolution 1n water togive an N 83 aqueous solution suitable for use as an antiseptic. Pre- 3O69 ferred compositions for use in dental hygiene are l 2 2 mouthwashescontaining between 0.05% and 0.5% w/v K A R First Second No A =A R=Rlinkage A linkage X=X l n-octyl 4 CH CH, 4 Ms 2 n-decyl 4 CH CH 4' Ms 3n-dodecyl 4 CH CH 4 Ms 4 n-octyl 4 (CH 4 Ms 5 n-decyl 4 (CH 4 Ms 6n-dodecyl 4 (CH:);, 4 Ms '7 n-tetra- 4 (CH 4 Br decyl 8 n-decyl 4-CH:CH- I 4 Ms 9 n-undecyl 4 CH:CH 4 Br l0 n-dodecyl 4 --CH:CH- 4 Ms 1|CH CO 3,4-di- 4 CH:CH- 4 CI NH" chlorophenyl l2 n-octyl 2 CH:CH 2 Ms l3n-decyl 2 CH:CH 2 Ms l4 n-octyl 3 CH:CH 3 Ms l5 n-decyl 3 CH:CH 3" Ms l6n-dodecyl 3 --CH:CH- 3 Ms l7 n-octyl 3 CH:CH 4 Ms l8 n-decyl 3 CH:CH 4Ms l9 Z-n-hexyl- 3 CH:CH- 4 Ms oxyethyl 20 4-.chloro- 3 CH:CH 4 Clbenzyl 2l 2.4-di- 3 CH:CH 4 Cl chlorobenzyl 22 2naphthyl 3 .CH:CH 4 Brmethyl 23 n-decyl 2 CH:CH 3 Ms 24 noctyl 3 -NH.CO.NH 3 Ms n-decyl 3NH.CO.NH 3 Ms 25 26 n-decyl 3 NH.CO.NH 3 Cl 27 ndecyl 3 NH.CO.CO.NH 3 Ms28 n-decyl 3 -NH.CO(CH 3 Ms CO.NH 29 'n-octyl 3 NH.CO(CH 3 Ms CO.NH- 3on-decyl 3 NH.CO(CH 3 Ms -continued First Second No. A'=A2 R'=R2 linkageA linkage" X=X2 3l n-octyl 3 NH.CO(CH2)E 3 Ms (301411-- 32 n-decyl 3 --1lH.CO(CH 3 Ms CO.NH 33 ndecyl 3 C1-1 .N11C0.NH. 3 Br 1-1 34 n-decyl 3CH2.NH.CO(CH,)2 3 Ms CO.NH.CH 35 n-decyl 3 Cl- .Nl-l.CO(Cl-l-,,) 3 MsCO.Nl-l.Cl-l 36 n-octyl 3 -Nl-l. CO 3 Ms 37 n-decyl 3 --Nl-l.CO 3 M5 38n-octyl 3 NH.CO 4 Ms 39 n-dccyl 3 NH.CO 4 Ms 40 n-octyl 3 -CH2.NH.CO- 3Ms 4] n-decyl 3 CH2.NH.CO 3 Ms 42 n-octyl 2 -CH 2.NH.CO 3 Ms 43 ndecyl 2-CH .Nl-l.CO- 3 Ms 44 n-octyl 3 -CH2.NH.CO 4 Ms 45 ndecy1 3 CH 1NHCO- 4Ms 46 n-octyl 2 -CH2.NH.CO 4 Ms 47 n-decyl 2 -CHZ.NH.CO 4 Ms 4% n-octyl4 C0.N1-1 C1-1 4 Ms Nl-LCO- 49 n-decyl 4 -CO.Nl-l(Cl-l 4 Ms Nl-l.CO 50n-decyl 4 CO.NH(CH2)6 4 MS NH.CO

'"linkage of left hand pyridine ring to A3 in the fonnula as written atthe head of the table. "where A3 is not symmetrical. it should be readas from left to right in the formula at the head of the table. "linkageof A to right hand pyridine ring in the formula as written at the headof the table. MFmethanesulphonate. "the methylene group is attached tothe pyridine nitrogen atom, and the NH group is attached to R.

Continued Reaction conditions 35 R i conditions Temperature TimeAdditive M.p.(C.) Temperature Time Additive M c No. C.) (mmutes) NO (CI)(minutes) 1 120 5 1 2-165 45 130 60 DIE 62-64 2 120 5 190-192 46 140 30DlE 171-174 3 155 265-267 47 130 30 DIE 89 92 (decomposition) 4O 48 16030 1315 1 7 4 120 10 61-63 49 165 30 DE 174-176 5 120 10 78-81 50 160 60DIE 59-61 6 120 87-89 7 130 1 5 83 36 ""approximate m.p., compound veryhygroscopic. 8 130 2Q1 2()5 DlE= di-isopmpylethylamine. 9 130 10 315-31710 130 10 236-238 45 11 140 1 255 y Certaln of the un-quatermsedpyndlnes, wherein A 12 140 60 is an amide containing linkage, used asstarting materi- 13 1 189492 als for the above compounds are novel, andmay be obg8 {3233: tained by the following process which exemplifies the[6 135 30 I 204408 50 preparation of the un-quaternised pyridinestarting ma- 38 ag-ft terial for compounds and 41: 19 130 10 I 5 1..)Nicotinoyl chloride (14.15 g.) was added over 10 20 95 5 248-250mlnutes, with stirring and cooling 1n an we bath, to a 21 130 5 224-229solution of 3-aminomethylpyridine (10.8 g.) and trieth- 22 130 4 273-27623 130 60 228431 ylamlne (10.1 g.) in methylene chloride ml.). After 52S8 2 193-1985 the addition was complete, the mixture was stirred at 26195 [0 im, 53:5: room temperature for an hour, diluted with water (10027 180 5 nitro- 239-243 ml. and the product was isolated from theorganic 28 I70 5 benfne 202404 5 phase by evaporation of the solvent.The crude product 59 160 5 186490 was recrystallised from ethyl acetate,m.p. lO4-106C. 0 150 5 203-206. 31 160 5 101403 5 The following startingmaterials were prepared 511111- 32 160 5 109.5-1105 larly, using theappropriate acid chlorides and amino 33 140 20 bn1tro Not crystallineCompounds;

enzene 34 150 1 98-100 3 5 15 131-134 15 DIE 157-160 37 140 30 DE168-[71 f Ffi 38 130 30 DIE 150-152 em M (T) 39 30 DIE 166-168 com dpoun s 40 30 DIE 68-69 nos. 41 140 30 DlE 167-169 42 130 30 DIE 158-16027 290-292 43 130 30 DlE 123-125 28 236-238 44 130 30 DlE 167-l70 233;30 232-235 3-Aminomethylpyridine (10.8 g.) and diphenyl car- -contmuedStarting material for M.p. ("0) compounds OS.

31, 32 161-164 34 196-2005 35 l84l85.5 38, 39 163-166 40, 41 104-106 42,43 75-78 44. 4s 7s s0 46, 47 83-85 bonate (10.7 g) were mixed, heatedtogether at 140C.

for 5 minutes, and the mixture was cooled and stirred 5 with ether. Theproduct was filtered off, washed with fresh ether, and recrystallisedfrom ethyl acetate, m.p.

prepared as follows:

The

EXAMPLE 2 process described in Example 1 is repeated,

using the appropriate bis-pyridine derivatives and quatemising agents,to give the following compounds:

-continued Reaction conditions No Temperature Time Additive M.p.( C.)

(C.) (minutes) 77 160 10 142-1445 78 150 60 sulpholane 2145-2165 79 14010 154-155 35 130 15 228-230 86 165 120 sulpholane 1 16-120 DIE 87 15060 sulpholane 213-2145 88 140 5 93.5-94.5 89 140 83-85 90 140 10 90 91190 134-136 92 1 50 15 72-74 93 155 5 197-199 94 180 10 162-166 95 18030 97-99 96 140 10 137-139 97 155 10 134-137 98 145 15 1 10-1 12 99 14030 DIE 90-93 "DIE di-isopropylethylamine.

A. Certain of the unquaternised pyridines, wherein A is anamide-containing linkage, used as starting materials for the abovecompounds are novel, and may be obtained from the reaction of anappropriate amine and an appropriate acid chloride by the processdescribed in the latter part of Example 1.

B. Certain other of the unquaternised pyridines,

wherein A is a ureido-containing linkage, used as starting materials forthe preparation of the above compounds of the invention, are novel andmay be obtained as follows:

A solution of hexamethylene di-isocyanate (1.68 g.) in toluene (10 ml.)was added to a solution of 3- aminopyridine (1.88 g.) in toluene (18ml.) and the mixture was heated on a steam-bath for 10 minutes. Themixture was cooled, and the product was filtered off, washed withtoluene and dried, to give l,6-bis[3- (pyrid-3-yl)ureido[hexane, m.p.197-199C., the starting material for compound 67.

In a similar manner, using3-aminomethylpyridine in place of3-aminopyridine, there was obtained the start,- ing material forcompound 68, 1,6-bis[3-(pyrid-3- ylrnethyl)ureido]-hexane, m.p.223-225C.

C. Certain other of the unquaternised pyridines, wherein A is a ureidoorurethane-containing linkage, used as starting materials for thepreparation of the above compounds of the invention, are novel and maybe obtained as follows: I

A solution of tetramethylene diamine (0.535 g.) in

toluene 10 ml.) was added with stirring and cooling to a solution of3-pyridyl isocyanate (1.46 g.) in toluene (15 ml.). The mixture wasstirred until the reaction was complete, and the product was filteredoff, washed with toluene and crystallised from ethanol to give1,4-bis[3- '(pyrid-3-yl)ureido]-hexane, mp. 218-2l9C., the

starting material for compound 66.

In a similar manner, using the appropriate isocyanate and theappropriate amine, diamine or diol, the following starting materialswere prepared:

EXAMPLE 3 The process described in Example 1 is repeated using theappropriate bis-pyridine derivates and quatemising agents, to give thefollowing compounds:

t indicates a trans double bond. "Me; methanesulphonate.

The unquaternised pyridine derivatives used as starting materials in thepreparation of compounds 100 and 101 are novel, may be prepared by theprocess described in the latter part of Example 1, and have meltingpoints of 32l.5-322.5C. and 1l7-1 19C. respectively.

The unquaternised pyridine derivatives used as starting materials in thepreparation of compounds 103 and 104 are novel, may be prepared by theprocess described at (C) in Example 2, and have melting points ofl2l-123C. and l94-l94.5C. respectively.

The unquaternised pyridine derivative used as starting material in thepreparation of compound 109 may be obtained as follows:

Sodium hydride (1.32 g.) was added portionwise under an atmosphere ofnitrogen during 30 minutes, to a stirred solution of 3-hydroxypyridine(2.85 g.) in dry dimethylsulphoxide (28 ml.) cooled to below C. Whenreaction ceased, 1,6-dibromohexane (3.66 g.) was added dropwise withstirring and cooling, and the resulting mixture was stirred a further 3%hours. The mixture was poured into ice-water, and the precipitatedproduct was filtered off and crystallised from petroleum ether (b.p.6080C.), to give 1,6-bis-pyrid-3- yloxyhexane, m.p. 85C.

In a similar manner, using the appropriate dibromides, there wereobtained the butane (m.p. 95C.) and decane (m.p. 64C.) analogues, thestarting materials for compounds 108 and 110 respectively.

EXAMPLE 4 cipitate the toluene-p-sulphonate salt, which was crystallisedfrom a mixture of acetone and acetonitrile,

The sulphate was prepared in similar manner, m.p. l46-l47C. v .3

The acetate (m.p. 8789C.) was prepared in similar manner, except thatthe new salt remained in the aqueous phase and was recovered byevaporation of the solvent and crystallisation of the residue fromacetone.

EXAMPLE 5 Compositions containing a pyridine derivative of the inventionmay be prepared from any pyridine of the invention described in theforegoing Examples by conventional procedures as illustrated below,where, it is to be understood, the particular pyridine derivative namedmay be replaced by an equipotent amount of any other pyridine derivativeof the invention. Lozenge A mixture of sucrose (92.5 a), magnesiumstearate (l g.), gum acacia (3 g.) water (3 ml.) and 3,3-suberamidobis(l-n-decylpyridinium chloride) (0.5 g.) is blended andcompressed into hard lozenges such that each weighs 1 g., and contains 5mg. of the antibacterial pyridine derivative.

Antiseptic 3,3 -Suberamidobis( l-n-decylpyridinium methanesulphonate)(0.5 g.) is dissolved in sterile distilled water (99.5 ml.) to give aliquid composition suitable for use as an antiseptic.

Toothpaste A'solution is prepared by stirring saccharin sodium (0.2 g.)in purified water (38.8 ml.) to which is then added isopropanol (4.0 g.)and. glycerin (20 g.) (Solution I).

A mixture of oil of peppermint (0.6 g.) and oil of spearmint (0.3 g.) isadded to Pluronic P (0.6 g. Pluronic is a trade mark) followed by 4,4-glutaramidobis( l-n-decylpyridinium methanesulphonate) (0.5 g.) andstirring is continued until a homogeneous solution is formed (SolutionII).

Solution 1 is slowly added to Solution ll, with stirring, and natrosol250Hl-l (l g. Natrosol is a trade mark) is then added, stirring beingcontinued until hydration is complete. A mixture of dicalcium phosphate(20 g.), Neosyl E.T. (10 g.), titanium dioxide (1 g.) and driedaluminium hydroxide gel (1 g.) is then addded and mixing is continueduntil a smooth and uniform paste is formed.

What we claim is:

1. A pyridine derivative of the formula:

20 acetate ions or the sulphate dianion; and A is a linking group of theformula:

NH-CO(CH2OCH2)2 CONH-.

2. The pyridine derivative of claim 1 wherein R and R are the same andare each n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl,n-undec-lO-enyl, Z-n-hexyloxyethyl, 2-(butoxyethoxy)ethyl, 3,4-dichlorophenyl, 4-chlorobenzyl, 2,4-dichlorobenzyl or 2-naphthylmethyl.

3. The pyridine derivative of claim 1 wherein A and A are each a directlinkage, R and R are each the same unbranched alkyl of 8 to 11 carbonatoms, (X X represents two bromide, chloride, methanesulphonate,toluene-p-sulphonate or acetate anions or the sulphate dianion, and A isa linking group of the formula:

4. A pyridine derivative as claimed in claim 1, said derivative being3,3'-(3,6-dioxa-l,8-octandiamido)bis l-n-decylpyridinium bromide).

1. A PYRIDINE DERIVATIVE OF THE FORMULA:
 2. The pyridine derivative ofclaim 1 wherein R1 and R2 are the same and are each n-octyl, n-nonyl,n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-undec-10-enyl,2-n-hexyloxyethyl, 2-(butoxyethoxy)ethyl, 3,4-dichlorophenyl,4-chlorobenzyl, 2,4-dichlorobenzyl or 2-naphthylmethyl.
 3. The pyridinederivative of claim 1 wherein A1 and A2 are each a direct linkage, R1and R2 are each the same unbranched alkyl of 8 to 11 carbon atoms, (X1 .X2)2 represents two bromide, chloride, methanesulphonate,toluene-p-sulphonate or acetate anions or the sulphate dianion, and A3is a linking group of the formula: -NH.CO(CH2OCH2)2CO.NH-.
 4. A pyridinederivative as claimed in claim 1, said derivative being3,3''-(3,6-dioxa-1,8-octandiamido)bis (1-n-decylpyridinium bromide).